Gestational trophoblastic disease (GTD) can
be benign or malignant. Histologically, it is classified
into hydatidiform mole, invasive mole (chorioadenoma
destruens), choriocarcinoma, and placental site
trophoblastic tumor (PSTT). Those that invade locally or
metastasize are collectively known as gestational
trophoblastic neoplasia (GTN). Hydatidiform mole is the most
common form of gestational trophoblastic neoplasia (see
Image 1). While invasive mole and choriocarcinoma are
malignant, a hydatidiform mole can behave in a malignant or
benign fashion.

No methods exist to accurately predict the
clinical behavior of a hydatidiform mole by histopathology.
The clinical course is defined by the patient's serum human
chorionic gonadotropin (HCG) curve after evacuation of the
mole. In 80% of patients with a benign hydatidiform mole,
serum HCG titers steadily drop to normal within 8-12 weeks
after evacuation of the molar pregnancy. In the other 20% of
patients with a malignant hydatidiform mole, serum HCG
titers either rise or plateau.

The official International Federation of
Gynecology and Obstetrics staging of gestational trophoblastic neoplasia is as follows:

Stage I – Confined to the uterus

Stage II – Limited to the genital
structures

Stage III – Lung metastases

Stage IV – Other metastases

Each stage is sub-classified further
according to a prognostic scoring index. If the risk factors
are unknown, no substage is assigned. If the prognostic
score is 7 or less, the substage is A (e.g., IIIA is equal
to lung metastasis with a prognostic score of 7 or less). If
the prognostic score is 8 or greater, the substage is B.

The currently used prognostic scoring index
is a modification of the World Health Organization (WHO)
classification. It provides points for the presence of a
number of prognostic factors, as follows:

Age 40 years or older = 1 point

Antecedent pregnancy terminated in
abortion = 1 point

Antecedent full-term pregnancy = 2 points

Interval of 4 months to less than 7
months between antecedent pregnancy and start of
chemotherapy = 1 point

Interval of more than 12 months between
antecedent pregnancy and start of chemotherapy = 4
points

Beta-HCG level in serum is 1000 mIU/mL
but less than 10,000 mIU/mL = 1 point

Beta-HCG level in serum is 10,000 mIU/mL
but less than 100,000 mIU/mL = 2 points

Beta-HCG level in serum is 100,000 mIU/mL
or greater = 4 points

Largest tumor is 3 cm but less than 5 cm
= 1 point

Largest tumor is 5 cm or greater = 2
points

Site of metastases is spleen or kidney =
1 point

Site of metastases is gastrointestinal
tract = 2 points

Site of metastases is brain or liver = 4
points

Number of metastases is 1-4 = 1 point

Number of metastases is 5-8 = 2 points

Number of metastases is more than 8 = 4
points

Prior chemotherapy with single drug = 2
points

Prior chemotherapy with multiple drugs =
4 points

Pathophysiology

Histologically, hydatidiform moles look like
placental tissue, but edema of the villi demonstrates
varying sizes. Proliferation of the trophoblast occurs, and
fetal blood vessels are lacking or are scarce.

If a fetus or fetal parts are present, this
is known as a partial or incomplete mole. Partial moles also
have malignant potential, but only 2% become malignant. An
invasive mole has the same histopathologic characteristics
of a hydatidiform mole, but invasion of the myometrium with
necrosis and hemorrhage occurs or pulmonary metastases are
present. Histologically, choriocarcinomas have no villi, but
they have sheets of trophoblasts and hemorrhage.

Choriocarcinomas are aneuploid and can be
heterozygous, depending on the type of pregnancy from which
the choriocarcinoma arose. If a hydatidiform mole preceded
the choriocarcinoma, the chromosomes are of paternal origin.
Maternal and paternal chromosomes are present if a term
pregnancy precedes the choriocarcinoma. Of choriocarcinomas,
50% are preceded by a hydatidiform mole, 25% by an abortion,
and the other 25% by a full-term pregnancy.

Placental site trophoblastic tumor is a rare
form of gestational trophoblastic neoplasm, with slightly
more than 200 cases reported in the literature. In patients
with PSTT, intermediate trophoblasts are found infiltrating
the myometrium without causing tissue destruction. The
intermediate trophoblasts contain human placental lactogen
(HPL). These patients have persistent low levels of serum
HCG (100-1000 mIU/mL). However, serum HCG titers as high as
58,000 mIU/ml have been reported in patients with placental
site trophoblastic tumors. The treatment of placental site
trophoblastic tumors is hysterectomy with ovarian
conservation. If the tumor recurs or metastases are present
at initial diagnosis, chemotherapy is administered with
variable results. Radiation therapy may provide local
control.

The most frequent sites of metastases of
malignant gestational trophoblastic neoplasm are the lungs,
lower genital tract, brain, liver, kidney, and
gastrointestinal tract.

Frequency

United States

Hydatidiform moles occur in 1 in 2000
deliveries, or 1 in 850 to 1 in 1300 pregnancies.

International

In Mexico, an incidence of 1 in 200
deliveries is reported, while an incidence of 1 in 120
deliveries is reported in Taiwan. Some believe these
international differences are due to differences in diet.
However, in some countries, these differences are due to
poor recording of the total number of deliveries, especially
if deliveries are normal and do not occur in a hospital.

Mortality/Morbidity

Patients who have a malignant hydatidiform
mole, an invasive mole, or a choriocarcinoma should undergo
a systematic search for metastases. Patients who have
metastases are classified as high-risk or low-risk according
to the National Institutes of Health classification. The
criteria for high-risk metastatic gestational trophoblastic
neoplasia include hepatic or brain metastasis, serum HCG
titers greater than 40,000 mIU/mL prior to the initiation of
chemotherapy, duration of disease longer than 4 months,
prior unsuccessful chemotherapy, and malignant gestational
trophoblastic neoplasia following a term pregnancy.

Patients with malignant non-metastatic or
metastatic low-risk gestational trophoblastic neoplasia
have an almost 100% probability of cure with
chemotherapy. The probability of cure after chemotherapy
for patients with metastatic high-risk gestational
trophoblastic neoplasia is approximately 75%.

The probability of a late recurrence
after the patient has been in remission (normal serum
beta-HCG titers) for 1 year is less than 1%.

Race

International reports are conflicting as
to whether ethnicity is an independent risk factor for
the development of gestational trophoblastic neoplasia.

In the United States, race does not
appear to be a risk factor.

Sex

Gestational trophoblastic neoplasia
affects women during their reproductive years. However,
placental site trophoblastic tumors have been diagnosed
when patients were postmenopausal.

Age

Hydatidiform mole is more frequent in
teenagers and in women older than 40 years. The
potential for malignant change is higher when a
hydatidiform mole occurs in a woman older than 40 years.

CLINICAL

History

Patients with a hydatidiform mole present
with signs and symptoms of pregnancy.

The most frequent symptom of
gestational trophoblastic neoplasia (GTN) is
abnormal uterine bleeding.

Patients have a history of
amenorrhea. Occasionally, the typical hydatid
vesicles (edematous villi) are passed through the
vagina.

Signs and symptoms of preeclampsia occur
in up to one third of patients.

Prolonged hyperemesis gravidarum is also
common.

Hyperthyroidism is found in up to 3% of
patients. This is due to the production of human molar
thyrotropin by the molar tissue and the similarities
between HCG and thyroid-stimulating hormone (TSH).

If metastases exist, signs and symptoms
associated with the metastatic disease, such as
hematuria, hemoptysis, abdominal pain, and neurologic
symptoms, may be present.

The more frequent use of early
obstetrical ultrasound has resulted in the earlier
diagnosis of hydatidiform mole prior to the onset of the
above signs and symptoms.

Physical

Suspect gestational trophoblastic
neoplasia when a positive pregnancy test result occurs
in the absence of a fetus.

Uterine size could be larger, smaller, or
equal to the estimated gestational age.

The identification of hydatid vesicles in
the vagina is diagnostic for hydatidiform mole.

Enlarged ovaries secondary to theca
lutein cysts are found in up to 20% of patients with
hydatidiform mole.

These cysts are the result of
stimulation of the ovaries by the high circulating
levels of HCG.

The cysts regress after evacuation of
the hydatidiform mole, but this process can take as
long as 12 weeks.

Causes

A hydatidiform mole occurs when a haploid
sperm fertilizes an egg that has no maternal chromosomes
and then duplicates its chromosomal complement.

Most complete hydatidiform moles are
46, XX, and all the chromosomes come from the male.

Of hydatidiform moles, 10-15% are 46,
XY. This occurs when 2 sperm, 1 carrying an X and
the other carrying a Y, fertilize an "empty" egg.

Partial moles are 69, XXY, and 2 sets of
chromosomes are of paternal origin.

Lab Studies

Serum HCG is elevated and frequently
higher than expected for the estimated gestational age.
A serum HCG greater than 100,000 mIU/mL should raise the
concern of gestational trophoblastic disease (GTD).

A CBC count may help detect anemia
secondary to vaginal bleeding.

Liver enzymes may become elevated in the
presence of metastasis to the liver.

Imaging Studies

Pelvic ultrasound

In the presence of an elevated serum
HCG titer, the absence of a fetus, and the
characteristic sonographic appearance ("snowstorm
pattern"), a hydatidiform mole is diagnosed.

Evacuation of the uterus is performed
with suction and sharp curettage.

The tissue is sent for
histopathologic examination.

Examination reveals a hydatidiform
mole (complete or partial) or a choriocarcinoma.

Rarely is a histopathologic diagnosis of
an invasive mole made on a dilation and curettage (D&C)
specimen because this requires the identification of
destructive invasion of the myometrium by the
trophoblasts. Scant or no myometrium is recovered on a
D&C specimen.

Histological Findings

Complete hydatidiform moles have edematous
placental villi, hyperplasia of the trophoblasts, and lack
or scarcity of fetal blood vessels.

In the incomplete or partial hydatidiform
mole, scalloping of the villi and trophoblastic inclusions
occur within the villi. Fetal blood vessels are present.

In a hydropic degeneration of a normal
pregnancy, edema of the villi is present, but no
trophoblastic hyperplasia. Ghost villi may be observed.

The invasive mole has the same appearance as
the hydatidiform mole, but the myometrium is invaded with
the presence of hemorrhage and tissue necrosis.

Although the choriocarcinoma has no chorionic
villi, it has sheets of trophoblasts, hemorrhage, and
necrosis. In the placental site trophoblastic tumors,
intermediate trophoblasts are found between myometrial
fibers, without tissue necrosis.

Patients with benign gestational
trophoblastic disease (GTD) do not require medical
therapy. Because 20% of patients with hydatidiform mole
develop malignant disease, such as persistent
hydatidiform mole with or without metastasis, some have
suggested the use of a prophylactic dose of methotrexate
(MTX) in noncompliant patients. However, observing
patients with weekly serum HCG titers is preferable, and
only patients with rising or plateauing titers, as
occurs in patients with malignant gestational
trophoblastic neoplasia (GTN), should be treated with
chemotherapy.

Patients with malignant nonmetastatic
gestational trophoblastic neoplasia or metastatic
low-risk gestational trophoblastic neoplasia are treated
with single-agent chemotherapy. Many in the United
States prefer MTX. However, actinomycin D can be used in
patients with poor liver function. During treatment, the
serum HCG titers are monitored every week. One
additional course of chemotherapy is administered after
a normal serum HCG titer. After 3-4 normal serum HCG
titers, the titers are followed once per month for 1
year. A switch from MTX to actinomycin D is made if the
patient receiving MTX for nonmetastatic or metastatic
low-risk gestational trophoblastic neoplasia develops
rising or plateauing serum HCG titers.

Patients with high-risk metastatic
gestational trophoblastic neoplasia are subdivided into
2 groups: those with a WHO score of less than 8 and
those with a score of 8 or higher and a high risk of
therapy failure.

·

In patients with a WHO score of less
than 8, a combination of MTX, actinomycin D, and
cyclophosphamide can be used. This is known as the
MAC regimen. This chemotherapeutic regimen is
administered every 19-21 days (from day 1 of the
previous chemotherapy cycle) until the serum HCG
titers normalize. In patients with a low WHO score,
one additional course of MAC is administered after a
normal serum HCG titer. Some prefer to treat these
patients with single-agent chemotherapy (MTX or
actinomycin) because their chances of achieving a
cure are high.

Patients with WHO scores of 8 or
higher are treated with a combination of etoposide,
MTX, and actinomycin D administered in the first
week of a 2-week cycle and cyclophosphamide and
vincristine administered in the second week. This is
known as the EMA-CO regimen. Some substitute
cisplatin and etoposide for cyclophosphamide and
vincristine during the second week. This is known as
the EMA-CE regimen. Some reserve the EMA-CE regimen
for patients in whom EMA-CO fails. Two additional
courses of EMA-CO or EMA-CE are administered after a
normal serum HCG titer in very high-risk patients.
Patients with metastasis to the brain receive whole
brain irradiation (3000 cGy) in combination with
chemotherapy. Corticosteroids (Decadron) with
systemic effect are administered to reduce brain
edema. Patients with liver metastasis are considered
for liver irradiation (2000 cGy).

Surgical Care

The treatment of a hydatidiform mole is
evacuation of the uterus by suction and sharp curettage.

·

To avoid excessive bleeding, oxytocin
is administered intravenously at the initiation of
the suctioning of the uterine contents.

The largest possible suction curette
is used, usually a 10F or 12F.

FOLLOW-UP

Further Outpatient Care

In patients with benign gestational
trophoblastic disease (GTD), who do not require
chemotherapy, obtain follow-up serum HCG titers once per
week until 3-4 normal values are obtained. Then, obtain
them once per month for 6 months. Have patients use
reliable contraception, such as oral contraceptives or
depot progesterone injections, during the period of
follow-up care.

Patients with malignant gestational
trophoblastic neoplasia should have follow-up serum HCG
titers once per week until 4 normal values are obtained.
Then, obtain them once per month for 1 year. Have
patients use a reliable method of contraception.

In/Out Patient Meds

During the period of follow-up care,
patients with gestational trophoblastic disease should
use a reliable method of contraception, such as oral
contraceptives or depot progesterone.

The serum HCG titers are critical in
monitoring the status of the disease, and a normal
intrauterine pregnancy interferes with this critical
monitoring tool.

Complications

Plateauing or rising serum HCG titers
during the period of follow-up care may indicate a
normal intrauterine pregnancy or gestational
trophoblastic neoplasia with or without metastasis.

Prognosis

Nonmetastatic gestational trophoblastic
neoplasia has a cure rate with chemotherapy of close to
100%.

Metastatic low-risk gestational
trophoblastic neoplasia has a cure rate with
chemotherapy of close to 100%.

Metastatic high-risk gestational
trophoblastic neoplasia has a cure rate with
chemotherapy of approximately 75%.

After 12 months of normal HCG titers,
less than 1% of patients with malignant gestational
trophoblastic neoplasia have recurrences.

Patient Education

The rate of occurrence of a repeat molar
pregnancy is approximately 1-2%.

The rate of occurrence of a repeat molar
pregnancy in a patient with a history of 2 previous
hydatidiform moles is approximately 10-20%.

The pregnancy rate after chemotherapy
with MTX and cyclophosphamide is 80%. Of women treated
with EMA-CO, 46% have had at least 1 live birth after
chemotherapy.

Patients who become pregnant after
treatment for gestational trophoblastic neoplasia should
have a pelvic ultrasound early during the pregnancy to
confirm that the pregnancy is normal.

Media file 1: Histological section of a complete
hydatidiform mole stained with hematoxylin and
eosin. Villi of different sizes are present. The
large villous in the center exhibits marked edema
with a fluid-filled central cavity known as
cisterna. Marked proliferation of the trophoblasts
is observed. The syncytiotrophoblasts stain purple,
while the cytotrophoblasts have a clear cytoplasm
and bizarre nuclei. No fetal blood vessels are in
the mesenchyme of the villi.